tbuckley/cabot-search huggingface dataset:
PB2305: EFGARTIGIMOD: CLINICAL DEVELOPMENT OF A NOVEL FCRN ANTAGONIST IN THE TREATMENT OF AUTOIMMUNE DISEASES
Authors: P. Knoebl, H. de Haard, W. Parys, P. Ulrichts, F. Rocca, A. Guglietta, J. Ayguasanosa
Journal: HemaSphere (2022)

Background: Immunoglobulin G (IgG) autoantibodies play a key role in the pathogenesis of various autoimmune diseases. The neonatal Fc receptor (FcRn) is the central regulator of IgG homeostasis, rescuing IgG (including pathogenic autoantibodies) and albumin from lysosomal degradation and is responsible for the long half-life of IgG. Therapeutic blocking of FcRn leads to reduction of all IgG subtypes without reducing other immunoglobulin types, making it a possible target for symptomatic treatment of autoimmune disorders, while maintaining normal immunological responses. Efgartigimod (EFG), an FcRn antagonist, is a human IgG1-derived Fc-fragment that outcompetes endogenous IgG binding, reduces IgG recycling, and increases IgG degradation. EFG is approved in the US and Japan for treatment of generalized myasthenia gravis (MG) in adult patients. Aims: This presentation provides an overview of EFG as a molecule and summarize the clinical development program to date. Methods: Studies in healthy volunteers and patients with autoimmune diseases are already completed. Phase 3 studies in immune thrombocytopenia (ITP; ADVANCE and ADVANCE SC) and phase 2/3 studies in chronic inflammatory demyelinating polyneuropathy (ADHERE), pemphigus vulgaris and foliaceus (ADDRESS), bullous pemphigoid (BALLAD), and myositis (ALKIVIA) are ongoing. Results: In a Phase 2 trial in patients with ITP, EFG (10 mg/kg given intravenously) reduced total IgG levels by 63.7% (from mean [SD] 10.6 g/L [5.1] at baseline to 4.1 g/L [2.0]) 3 days after the fourth weekly infusion. No changes in IgG levels were observed in patients treated with placebo during that time. These reductions led to clinically relevant increases in platelet counts; 46% of EFG patients vs 25% on placebo achieved a platelet count of ≥50 x109/L on ≥2 occasions. In a Phase 3 trial in MG (ADAPT), EFG rapidly reduced IgG without impacting IgM, IgA, or albumin levels while participants recorded statistically significant functional neurological improvements. In all studies to date, EFG was well tolerated, and adverse events were mainly mild to moderate. Summary/Conclusion: FcRn inhibition by EFG is a promising potential therapeutic option for several autoimmune diseases mediated by pathogenic IgG autoantibodies.
Abstract LB119: Precision combination therapies based on recurrent oncogenic co-alterations
Authors: Anil Korkut, Xubin Li, Elizabeth Kong, Gonghong Yan, Zeynep Dereli, Behnaz Bozorgui, Parisa Imanirad, Jacob Elnaggar, Augustin Luna, David Menter, Patrick Pilié, Timothy Yap, Scott Kopetz, Chris Sander
Journal: Cancer Research (2022)

Abstract Cancer cells depend on multiple driver alterations whose oncogenic effects can be suppressed by drug combinations. Discovering effective combination therapies and selecting patients to maximize therapeutic benefit are challenging due to the complexity of the molecular landscape of drug responses. Here, we provide a comprehensive resource of precision combination therapies tailored to oncogenic co-alterations that are recurrent across patient cohorts. To generate the resource, we developed REcurrent Features Leveraged for Combination Therapy (REFLECT), which integrates machine learning and cancer informatics algorithms. Based on multi-omic data, the method maps recurrent co-alteration signatures in patient cohorts to combination therapies. The resource matches &amp;gt; 2,000 drug combinations to co-alteration signatures across 201 cohorts stratified from 10,392 patients and 33 cancer types. We validated the REFLECT pipeline using data from patient-derived xenografts (PDX), in vitro drug screens, and combination therapy clinical trials. These validations demonstrate that REFLECT selects combination therapies with significantly improved efficacy, drug synergy, and survival outcomes. In patient cohorts with immunotherapy response markers, HER2 activation, and DNA repair aberrations, we have identified therapeutically actionable and recurrent co-alteration signatures. REFLECT provides a resource and framework to design combination therapies tailored to tumor cohorts in data-driven clinical trials and pre-clinical studies. Citation Format: Anil Korkut, Xubin Li, Elizabeth Kong, Gonghong Yan, Zeynep Dereli, Behnaz Bozorgui, Parisa Imanirad, Jacob Elnaggar, Augustin Luna, David Menter, Patrick Pilié, Timothy Yap, Scott Kopetz, Chris Sander. Precision combination therapies based on recurrent oncogenic co-alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB119.
PB2326: SAFE AND EFFECTIVE PROPHYLAXIS WITH PLASMA-DERIVED FACTOR X CONCENTRATE IN AN ELDERLY PATIENT WITH HEREDITARY FACTOR X DEFICIENCY
Authors: H. Patel, S. Peltier, K. Clark, M. T. Reding
Journal: HemaSphere (2022)

Background: Coagulation factor X, human is a plasma-derived factor X concentrate indicated to treat and prevent bleeding in individuals with hereditary factor X deficiency (HFXD). The ages of patients in whom data was collected in the initial registration trials and post-marketing studies ranged from 0-58 years. To date, there have been no reports on treatment of elderly (>65 years) patients with plasma-derived factor X (pdFX) concentrate. Aims: To report the experience with pdFX concentrate in the prophylactic treatment of HFXD in a patient >65 years. Methods: Data was collected on a 71-year-old female with HFXD receiving prophylactic treatment with pdFX. Results: Although suspected to have some type of bleeding disorder since age 2, this individual was not diagnosed with HFXD until age 20. Initial treatment included fresh frozen plasma on-demand for acute bleeding episodes. Subsequent treatment included three-factor prothrombin complex concentrate (PCC), starting in the 1990s. Prophylactic treatment was started at age 57 after she developed a spontaneous subdural hematoma. She was transitioned from PCC to pdFX prophylaxis in November 2019 to more directly address her factor X deficiency and to avoid increasing other clotting factor levels above the normal range. She is currently receiving pdFX 21 units/kg weekly, which has been well tolerated and she has experienced no bleeding issues since starting this therapy. Summary/Conclusion: This is the first reported experience of prophylactic treatment of an elderly patient with pdFX. Additional details of this case including laboratory data and updates from her recent clinic visit(s) will be presented. The data supports the successful prophylactic treatment of elderly patients and the need to continue to collect data in this population of patients with this rare bleeding disorder.
P1671: GENES POLYMORPHISM OF THROMBOPHILIA AND PROTHROMBOTIC CONDITIONS IN WOMEN WITH VARIOUS OBSTETRIC ANAMNESIS
Authors: A. Zagarskikh, E. Butina
Journal: HemaSphere (2022)

Background: Reproductive failure is one of the leading problems in modern obstetrics and gynecology. Causes of fertility disorders are diverse, but a particular place among them is thrombophilia, as hereditary and acquired. Given the peculiarities of the physiological adaptation of the haemostatic system to pregnancy, the vast majority of genetic thrombophilia is clinically manifested during the gestational process, both in the form of thrombosis, as well as in the form of common obstetric complications. Aims: Specify the role of genes for thrombophilia and prothrombotic conditions (F2: 20210 G>A, F5: 1691 G>A, F7:10976 G>A, F13: 103 G>T, FGB: -455 G>A, ITGA2: 807 C>T, ITGB3: 1565 T>C, PAI-1: -675 5G>4G) in the development of reproductive failure in women. Methods: The distribution of the hemostasis system genes in 198 women was analyzed: 84 women with recurrent pregnancy loss (ICD-10: N96) with 3 or more missed abortions (anatomical, gynecological, infectious and endocrine aggravating factors are excluded). The comparison group consisted of 114 women without obstetric and gynecological complications, with two or more urgent deliveries. The women’s age ranged from 27 to 49 years (median 38 years). The study was carried out with reagents and equipment of “DNA Technology”, Russia). For statistical processing of data was used criterion χ2. Results: The frequency of occurrence of thrombophilia and prothrombotic genes polymorphism are presented in the Table. Tab l. - Thrombophilia and prothrombotic alleles polymorphism in women with various obstetric history (%) Polymorphism Genotypes Women with recurrent pregnancy loss (n=84) Comparison group(n=114) F2: 20210 G>A G/G 100.0 97.4 G/A+А/А 0 2.6 F5: 1691 G>A G/G 96.4 94.7 G/A+A/A 3.6 5.3 F7: 10976 G>A G/G 84.3 78.9 G/A+A/A 15.7 21.1 F13: 103 G>T G/G 48.8 45.6 G/T+T/T 51.2 54.4 FGB: -455 G>A G/G 65.5 51.8 G/A+A/A 34.5 48.2 ITGА2: 807 C>T C/C 42.0 40.6 C/T+T/T 58.0 59.4 ITGВ3: 1565 T>C T/T 71.4 77.2 T/C+C/C 28.6 22.8 PAI-1: -675 5G>4G 5G/5G 13.1 16.7 5G/4G+4G/4G 86.9 83.3 The data of our study showed that there were no differences in the distribution of polymorphism of genes associated with thrombophilia and prothrombotic conditions between the group with recurrent pregnancy loss and the comparison group (p>0.05). Summary/Conclusion: The study did not establish the influence of polymorphism of the hemostasis system genes (F2: 20210 G>A, F5: 1691 G>A, F7: 10976 G>A, F13: 103 G>T, FGB: -455 G>A, ITGA2: 807 C>T, ITGB3: 1565 T>C, PAI-1: -675 5G>4G) for miscarriage. Thus, the role of allelic variants of the hemostasis system genes in fertility disorders, in our opinion, is overestimated, and these pathologies are associated with other causes.
P1620: RED CELL ALLOIMMUNIZATION IN MULTI-TRANSFUSED TURKISH PATIENTS WITH HEMATOLOGIC DISORDERS.
Authors: S. Oztaskin, M. Yanasik, M. Ozbalak, M. Guzel Mastanzade, O. Ozluk, T. O. Tiryaki, S. Erdem, S. Besisik
Journal: HemaSphere (2022)

Background: The red blood cell (RBC) alloimmunization rate varies with underlying disorder among genetic diversity of the population and environmental influences. Aims: The aim of this study was to determine the RBC alloimmunization rate in multi-transfused patients with hematological disorders in Turkey as a country with different ethnic groups covering a mixture of European and Asian DNA. Methods: The study was designed retrospectively. The research group consists 148 newly diagnosed hematological malignancy patients as candidates for multiple transfusion. Pre-transfusion tests included indirect anti-globulin test (IAT) with gel centrifugation among ABO Rh blood grouping and cross-match. Antibody identification test was applied to patients with positive IAT after direct antiglobulin tests was found to be negative. Results: Of the 148 patients 53.4% (n=79) were male and 46.6% (n=69) were female. The mean age of the patients was 53.03±17.78. IAT proved to be in 22 patients (14.9%) positive. In 6 of them alloantibody determining test was not performed (not ordered by the clinician). In 9 patients alloantibody type could not be determined. In the remaining’s (43.8%) the most frequent alloantibody types were against Rh antigens and anti-E was found to the most common encountered (12.5%) antibody. In three patients, more than one antibody type was detected. Summary/Conclusion: Our study is from the largest city from Istanbul as a tertiary hospital in Turkey. Apart of different antigenic exposure and microenvironment of underlying disorder, the general ethnic background of the country may be an influencer for the results. New molecular researchs including HLA and immune response analysis would be more definitely clear the alloimmunization development.
P1663: THE EFFECTS OF OBESITY ON BLEEDING FREQUENCY AND PARAMETERS OF FIBRINOLYSIS IN PATIENTS WITH NON-SEVERE HEMOPHILIA
Authors: O. Königsbrügge, J. Rejtö, D. Kraemmer, G. Schuster, C. Feistritzer, J. Gebhart, C. Ay, I. Pabinger
Journal: HemaSphere (2022)

Background: Obesity leads to increased strain on muscles and joints and could be a contributing factor to the burden of disease in patients with non-severe hemophilia. Fatty tissue, however, also plays an active part in the production of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) and is considered to transition the balance of hemostasis towards a reduction of fibrinolysis. Aims: We aimed to investigate the effects of obesity on the frequency of bleeding and changes in parameters of fibrinolysis in persons with non-severe hemophilia. Methods: Persons with non-severe hemophilia A or B (PwH) were recruited into a cross-sectional cohort study after informed consent. Frequency of bleeding in the past 5 years was retrospectively recorded. Body-mass index (BMI), FVIII or IX activity, t-PA antigen and activity, and PAI-1 activity were measured. Results: The cohort includes 90 PwH (74 hemophilia A, 16 hemophilia B) with a median age of 49.6 years (25th to 75th percentile 34.5–59.9), and a median FVIII/FIX level of 12% (8–19%). The median BMI was 25.7 kg/m^2 (23.3–28.3), and 14 patients (15.5%) had BMI>30. The median number of bleeding episodes in the past 5 years was 0 (0-1). In age-adjusted negative binomial regression, factor VIII/IX level (incidence rate ratio [IRR] 0.93 per 1% increase, 95% confidence interval [CI] 0.88-0.98, p<0.001), and BMI (IRR 0.82 per 1kg/m^2 increase, 95%CI 0.74-0.91, p<0.001) were independently associated with frequency of bleeding episodes. Factor VIII/IX levels (IRR 0.88, 95%CI 0.80-0.96, p=0.005) and BMI (IRR 0.68, 95%CI 0.55-0.82) were also independently associated with the frequency of joint and muscle bleeding. BMI correlated with PAI and t-PA antigen levels (rho 0.241, p= 0.025 and 0.257, p= 0.017) and correlated inversely with t-PA activity (rho -0.240, p=0.026). Summary/Conclusion: While level of FVIII or FIX are the main determinants of bleeding severity, there is considerable heterogeneity in the bleeding phenotype irrespective of factor level. We found that in non-severe hemophilia patients, increasing BMI decreased the number of bleeding episodes and joint and muscle specific bleeding episodes. The bleeding severity was potentially mitigated by increasing PAI levels and decreasing t-PA activity.
P1341: HAPLO-CORD VS HAPLOIDENTICAL TRANSPLANT IN 49 CHILDREN – A RETROSPECTIVE SINGLE CENTER ANALYSIS
Authors: P. Fu, K. Chen, J. Shao, Q. Liu, N. Zhang, B. Zou, X. Sun, H. Jiang
Journal: HemaSphere (2022)

Background: Haplo-cord transplantation means that umbilical cord blood grafts from unrelated donors are infused together with CD34+-selected cells selected from Haploidentical relatives, which avoids the delayed implantation and long initial hospital stay caused by umbilical cord blood transplantation, and provides an effective alternative for patients without suitable donors. Some studies showed that haplo-cord transplantation could lead to faster neutrophil recovery and lower incidence of chronic GVHD compared with haplo transplantation. In order to make full use of the advantages of easy access to grafts and possibly reducing the incidence of chronic GVHD, we have adopted haplo-cord program to some children lacking suitable donors, and reported the outcome of haplo-cord transplantation, comparing Virus reactivation,the incidence rate of acute and chronic GVHD, and 3-year overall survival rate with haplo-SCT. Aims: To compare the outcome of haplo-cord transplantation program with haplo transplantation. Methods: 35 children with Haplo-cord transplantation and 14 children with Haplo-SCT in our hospital were followed up between May 2017 and May 2021, the engraftment, immune reconstitution,Virus reactivation, incidence of GVHD and 3-year overall survival rate were observed. Results: The median time of neutrophil recovery in both groups was 13 days, and the cumulative recovery rate of neutrophils on the 30th day was 100%. By day 15,85.7% of the haplo-cord recipients had recovered neutrophil counts vs 92.7% of haplo recipients (P= 0.8). The median time of platelet recovery in both groups was 17 days, and no primary graft failure was observed in all patients. Secondary graft failure was documented in 5 haplo-cord recipients and 2 haplo recipients. 17 patients developed CMV-DNAemia in haplo-cord transplant and 9 in haplo patients. 31 cases had EB-DNAemia in haplo-cord vs 10 in haplo patients.By day 100, the cumulative incidence of acute GVHD in Haplo-cord patients was 25.7% vs 28.5% in haplo patients (P=1), and the cumulative incidence of grade 3-4 acute GVHD by day 100 was 11.4% vs 21.4% respectively (P = 0.65). There were no acute GVHD related deaths. Chronic GVHD was significantly reduced in haplo-cord with a cumulative incidence of 5.7% vs 28.6% in haplo patients by 1 year (P =0.04), but no extensive chronic GVHD was observed. The 3-year overall survival rate was 84.5% in haplo-cord transplant vs 74.3% in haplo transplant(P=0.98). Summary/Conclusion: Haplo-cord transplantation has high implantation rate and good long-term prognosis, and the incidence of chronic GVHD is significantly reduced, which provides an alternative for patients lacking Human leukocyte antigen-matched sibling donor and HLA-matched unrelated donor.
P1670: LONG TERM SAFETY AND EFFICACY OF RECOMBINANT HUMAN COAGULATION FACTOR VIII (SCT800) IN PREVIOUSLY TREATED PATIENTS WITH SEVERE HEMOPHILIA A
Authors: F. Xue, X. Zhao, J. Sun, X. Zeng, F. Yang, M. Xu, Z. Yu, W. Gu, Y. Feng, W. Li, C. Zheng, H. Bi, C. Ma, W. Gai, L. Xie, R. Yang
Journal: HemaSphere (2022)

Background: SCT800 (Omfiloctocog alfa) is the first domestic recombinant factor VIII approved in China based on pivotal study NCT03815318. The extension study (NCT03947567) is ongoing to evaluate the long term safety and efficacy in previously treated patients (≥12 years) with severe hemophilia A. Aims: To report the interim data for the extension study. Methods: Patients who completed the main study enrolled in the open‐label extension study and continued receiving 25-50 IU/kg SCT800 every other day or three times weekly. The primary endpoint was development of inhibitors; the key secondary endpoints included median annualized bleeding rate (ABR). Results: As of 24 Feb 2022, no inhibitors were observed in total 69 enrolled patients with a median exposure of 332 days (range 79-432 days). Adverse reactions occurred in 4.3% of the patients and SAEs were reported in 4 patients (5.8%). Median ABR (IQR) for all bleeds was 2.00 (4.10) in the pivotal study and 0.48 (1.46) during the extension (Table). Of the 178 reported bleeds, hemostatic efficacy was rated as “Excellent” or “Good” for 88.8% of the events. Improved joint function was observed in 67 patients with a mean total HJHS scores decreased by 3.4. Image:Summary/Conclusion: The interim data demonstrate favorable long-term safety of SCT800 and the maintenance of low ABR in patients with severe hemophilia A.
PB1912: MYELODYSPLASTIC SYNDROME WITH ISOLATED 5Q DELETION AND ASSOCIATED 5Q DELETION TO 13Q DELETION
Authors: N. Bouayed Abdelmoula, B. Abdelmoula, A. Karra
Journal: HemaSphere (2022)

Background: The 5q deletion is the classic chromosomal abnormality in myelodysplastic syndrome (MDS). Critical regions are 5q31 and 5q33, leading to gene haplodeficiency and other pathogeneic mechanisms. 13q deletion occurs in about 2% of MDS cases. This deletion involved band 13q14. Aims: Here we describe cytogenetic abnormalities in a Tunisian cohort of MDS patients and we shed the light on cases with 5q deletion. Methods: Cytogenetic analyses of bone marrow cells were performed according to standard procedures for 12 Tunisian patients presenting with MDS. Cytogenetic analysis was performed on lymphocytes and bone marrow cells. Cultured cells were treated with colchicine and hypotonic KCl solution. The pellet was fixed and washed in methanol-acetic acid (3:1). The cells were resuspended in fixative and dropped onto slides. Chromosome-banding analysis was performed using RHG and GTG banding techniques. Three karyotypes and 25 metaphases were analyzed according to the International System for Human Cytogenetic Nomenclature. Results: Cytogenetic abnormalities were detected in 9 cases and del5q was recorded in four patients (3 patients with refractory anemia (RA) and a fourth with RA and excess blasts-T (RAEB-T)). The del5q was isolated in two RA cases as a del (5) (q13 q33) in a new diagnosed and a treated patients. It was associated in two patients: a RA patient explored during the evolution, harboring a del (5) (q12 q33) associated to a del (13) (q12 q14) and the RAEB-T patient harbouring a del (5) (q21 q31) associated to a clonal hyperploidy. Summary/Conclusion: The diagnosis of MDS was based on cytomorphology and cytogenetics. However, nowadays, an increasing number of molecular aberrations have been discovered and included in the WHO revised new classification of myeloid neoplasms. The del13q described in MDS seems to be a marker of the evolution of the clonal cells harboring 5q deletion. However, the molecular basis and the implicated genes of the deletion of the long arm of chromosome 13 associated to the 5q deletion clone remain until now not well explored.
PB2284: PROTECTION OF PATIENTS WITH HEMATOLOGIC MALIGNANCY FROM SEVERE INFECTION DURING PANDEMIA: ESTONIAN TWO CENTRES EXPERIENCE
Authors: I. Vaide, V. Aabrams, E. Laane
Journal: HemaSphere (2022)

Background: In the course of lymphoproliferative diseases, an immunodeficiency of humoral or cellular origin has been described. Infectious complications of common or atypical origin alter patients’ lifestyles or result in severe, life-threatening hospitalizations. Hematology patients are prone to opportunistic infections after viral infection. In Estonia, chemotherapy for haematological patients is mainly covered in two regional centers in Tartu (University Hospital) and in Tallinn. The outpatient consultations are also covered in other parts of Estonia. In times of pandemic, when lockdowns are changing the situation and it has been difficult to travel to large centers, local hematology care needs for high-risk hematology elderly patients are growing. Aims: In the case of lymphoproliferative diseases, a secondary immune deficiency with severe infections can develop during the course of therapy, which is objectively discovered by immunoglobulin testing (IgG), and replased by immunoglobulin substitution. According to Kreuth IV, the value for prophylactic IgG replacement therapy is below 4g/l Methods: Review of the 20 case records of the two hospitals in Estonia, in Pärnu and in Kuressaare. Results: There are in regulare treatment or watching in Pärnu center and in Kuressaare center about 80 patients with lymphoproliferative disease. From them needed according to IgG status below 7(ref 7-16) 20 patients. The mean age of patisents is 70.8 (range 38-89). The mean basic IgG (ref 7-16) in patients in Immunoglobulin treatment is 4,49 (range 3.3-6).The intervall for prophylactic replasment was 4.6 or 8 weeks in 20 patients. From those 8 patients had SARS-Cov2 during this period, no patient was dying because of SARS-Cov2 infection and in 4 patients there was SARS-COV2 IgG pos later, in one patients SARS-COV2 IgG was negative afther the severe infection, in 3 patients is SARS-COV2 IgG not known afther frecovery from disease. Two patents died: one of secondary Pulm tumor related infection and one of sigmoidal ca, who had 6 months earlyer COVID19 severe infection. From 20 patients 9 diceided to have vaccination and 6 got no SARS-COVIgG antibodyes afther that. All patients had during 01.06.2019- 01.02. 2022 years in some period immunosupressive treatment. Summary/Conclusion: We recommend the individualized protection of vulnerable hematologyc diseases patients with long-term illness. Secondary immunodeficient patients need during pandemic when hospital beds are overgrown immunoglobulin replasmenttherapy to prevent their unneccesary hospitalization.